The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence

Abstract

Previous work in our laboratories provides preclinical evidence that mixed-action delta/mu receptor glycopeptides have equivalent efficacy for treating pain with reduced side effect profiles compared to widely used mu agonist analgesics such as morphine. This study evaluated the rewarding and reinforcing effects of a lead candidate, mixed-action delta/mu agonist MMP-2200, using a conditioned place preference assay as well as a drug self-administration procedure in rats. In place conditioning studies, rats underwent a 2-week conditioning protocol and were then tested for chamber preference. Rats receiving MMP-2200, at previously determined analgesic doses, could not distinguish between the drug and saline-paired chamber, whereas rats receiving the opioid agonist morphine showed a strong preference for the morphine-paired chamber. In self-administration studies, rats were trained to respond for the high efficacy mu opioid receptor agonist fentanyl on an FR5 schedule of reinforcement. Following complete dose-response determinations for fentanyl, a range of doses of MMP-2200 as well as morphine were tested. Relative to the mu agonist morphine, MMP-2200 maintained a significantly lower number of drug infusions. To begin investigating potential molecular mechanisms for the reduced side effect profile of MMP-2200, we also examined βarrestin2 (βarr2) recruitment and chronic MMP-2200 induced cAMP tolerance and super-activation at the human delta and mu receptors in vitro. MMP-2200 efficaciously recruited βarr2 to both receptors, and induced cAMP tolerance and super-activation equivalent to or greater than morphine at both receptors. The in vivo findings suggest that MMP-2200 may be less reinforcing than morphine but may have some abuse potential. The reduced side effect profile cannot be explained by reduced βarr2 recruitment or reduced cAMP tolerance and superactivation at the monomeric receptors in vitro.

Evaluation of morphine‐like effects of the mixed mu/delta agonist morphine‐6‐O‐sulfate in rats: Drug discrimination and physical dependence

“…Although the similar withdrawal-like naltrexone-elicited effects on food-maintained responding were unexpected, it remains the case that dependence on M6S may have developed more slowly with M6S than with morphine. In that regard, similar results have been observed with a mixed l/d opioid glycopeptide, 37,47 where it was suggested that heterodimerization of l/d opioid receptors (modulating neuronal network effects of l-and d-containing neurons at a level above the individual receptor) or additional cellular regulators in neurons could modulate the induction of tolerance and dependence at the receptor level, slowing tolerance development. Indeed, it has been previously reported that drugs with affinity for l and j opioid receptors demonstrated different results across tests of thermal nociception, schedule-controlled responding and drug self-administration, and our previous and present reports with the mixed l/d opioid agonist M6S contributes to this growing body of literature demonstrating that novel drug-receptor interactions may elicit distinct effects across experimental endpoints (e.g.…”

“…One common adverse effect limiting the chronic use of μ opioid agonists is their notorious liability for abuse, physical dependence, and addiction . Prescription μ opioids are not only abused, but are also responsible for severe morbidity and death from overdose . The present report provides an initial characterization of the morphine‐like discriminative stimulus effects and physical dependence properties of the novel mixed‐action μ/δ opioid M6S in rats.…”

“…35 Prescription l opioids are not only abused, but are also responsible for severe morbidity and death from overdose. 36,37 The present report provides an initial characterization of the morphine-like discriminative stimulus effects and physical dependence properties of the novel mixed-action l/d opioid M6S in rats. Here we demonstrate that, unlike morphine and fentanyl, M6S did not fully substitute for morphine in drug discrimination, although this is likely due to the limited dose range tested.…”

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

“…Accordingly, much effort has been dedicated to the development of new MOR agonists retaining potent analgesic effects, while mitigating or eliminating the deleterious side effects of the agents currently in use. 1–8 …”

Unlike Morphine, Long-Term Exposure to Analgesic Mitragynine, 7-Hydroxymitragynine, Paynantheine, and Speciociliatine Alkaloids Does Not Contribute to Antinociceptive Tolerance of μ-Opioid Receptors

“…Recent studies have investigated the pathways correlated with tolerance mechanisms in these receptors, especially in the face of morphine. Activation of β-arrestin-2, ERK1/2, and phosphorylated counterpart of ERK1/2 proteins was proved to be the most signaling pathways leading to µ-receptor downregulation and nally, drug dependence and antinociceptive tolerance [6][7][8].…”